Please cite this article in press as: Levin, K.H., et al., Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers. Drug Alcohol Depend. (2010), doi:10.1016/j.drugalcdep.2010.04.010 ARTICLE IN PRESS G Model DAD-3801; No. of Pages 8 Drug and Alcohol Dependence xxx (2010) xxx–xxx Contents lists available at ScienceDirect Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep Full length article Cannabis withdrawal symptoms in non-treatment-seeking adult cannabis smokers Kenneth H. Levin a,1 , Marc L. Copersino b , Stephen J. Heishman a , Fang Liu c , Deanna L. Kelly c , Douglas L. Boggs c , David A. Gorelick a,∗ a Intramural Research Program, National Institute on Drug Abuse, 251 Bayview Blvd., Baltimore, MD 21224, USA b McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA c Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA article info Article history: Received 4 December 2009 Received in revised form 8 April 2010 Accepted 11 April 2010 Available online xxx Keywords: Cannabis Marijuana Withdrawal Tolerance Relapse abstract Background: Cannabis withdrawal is not recognized in DSM-IV because of doubts about its clinical sig- nificance. Objectives: Assess the phenomenon of cannabis withdrawal and its relationship to relapse in non- treatment-seeking adults. Subjects: Convenience sample of 469 adult cannabis smokers who had made a quit attempt while not in a controlled environment. Methods: Subjects completed a 176-item Marijuana Quit Questionnaire collecting information on sociode- mographic characteristics, cannabis use history, and their “most difficult” cannabis quit attempt. Results: 42.4% of subjects had experienced a lifetime withdrawal syndrome, of whom 70.4% reported using cannabis in response to withdrawal. During the index quit attempt, 95.5% of subjects reported ≥1 individual withdrawal symptom (mean [SD] 9.5 [6.1], median 9.0); 43.1% reported ≥10. Number of withdrawal symptoms was significantly associated with greater frequency and amount of cannabis use, but symptoms occurred even in those using less than weekly. Symptoms were usually of ≥ moderate intensity and often prompted actions to relieve them. Alcohol (41.5%) and tobacco (48.2%) were used more often than cannabis (33.3%) for this purpose. There was little change during withdrawal in use of other legal or illegal substances. Conclusions: Cannabis withdrawal is a common syndrome among adults not seeking treatment. The inten- tion to relieve withdrawal symptoms can drive relapse during quit attempts, giving cannabis withdrawal clinical significance as a target of treatment. Published by Elsevier Ireland Ltd. 1. Introduction Cannabis is the most widely used illicit psychoactive substance in the world. An estimated 142–190 million people used cannabis in 2007 (3.3–4.4% of the population aged 15–64 years), about 10% of whom were dependent (United Nations Office on Drugs and Crime, 2009). In the United States, there were an estimated 15.2 million current (past month) cannabis users in 2008 (6.1% of the population 12 years or older), of whom 4.2 million met DSM-IV criteria for abuse or dependence (Substance Abuse & Mental Health Services Administration, 2009). A majority of these current users have not ∗ Corresponding author at: National Institute on Drug Abuse, National Institutes of Health, Intramural Research Program, 251 Bayview Boulevard, suite 200, Baltimore, MD 21224, USA. Tel.: +1 443 631 8004; fax: +1 443 631 8037. E-mail address: [email protected](D.A. Gorelick). 1 Currently at Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112, USA. sought treatment to stop their cannabis use (Stinson et al., 2006). Research has now established withdrawal from cannabis as a distinct clinical phenomenon (Budney, 2006; Budney and Hughes, 2006). This research has used several approaches, including ret- rospective self-report studies (Copersino et al., 2006a; Hasin et al., 2008), prospective outpatient self-report studies (Budney et al., 2003; Kouri and Pope, 2000; Vandrey et al., 2008), prospec- tive inpatient observational studies (Milin et al., 2008), and human laboratory studies of directly observed cannabinoid administration and abstinence (Haney et al., 1999; Jones et al., 1976, 1981; Nowlan and Cohen, 1977). All these approaches demonstrate distinct with- drawal symptoms following abrupt cessation of cannabis use. Furthermore, these abstinence symptoms resolve with cannabi- noid re-administration (Budney et al., 2007; Haney et al., 2004, 2008; Jones et al., 1981), a key characteristic of a drug withdrawal syndrome. More than a dozen studies have retrospectively evaluated the prevalence of individual symptoms of cannabis withdrawal over a 0376-8716/$ – see front matter. Published by Elsevier Ireland Ltd. doi:10.1016/j.drugalcdep.2010.04.010
Transcript
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ARTICLE IN PRESSModel
AD-3801; No. of Pages 8
Drug and Alcohol Dependence xxx (2010) xxx–xxx
Contents lists available at ScienceDirect
Drug and Alcohol Dependence
journa l homepage: www.e lsev ier .com/ locate /drugalcdep
ull length article
annabis withdrawal symptoms in non-treatment-seekingdult cannabis smokers
enneth H. Levina,1, Marc L. Copersinob, Stephen J. Heishmana, Fang Liuc,eanna L. Kellyc, Douglas L. Boggsc, David A. Gorelicka,∗
Intramural Research Program, National Institute on Drug Abuse, 251 Bayview Blvd., Baltimore, MD 21224, USAMcLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USAMaryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA
r t i c l e i n f o
rticle history:eceived 4 December 2009eceived in revised form 8 April 2010ccepted 11 April 2010vailable online xxx
eywords:annabisarijuanaithdrawal
oleranceelapse
a b s t r a c t
Background: Cannabis withdrawal is not recognized in DSM-IV because of doubts about its clinical sig-nificance.Objectives: Assess the phenomenon of cannabis withdrawal and its relationship to relapse in non-treatment-seeking adults.Subjects: Convenience sample of 469 adult cannabis smokers who had made a quit attempt while not ina controlled environment.Methods: Subjects completed a 176-item Marijuana Quit Questionnaire collecting information on sociode-mographic characteristics, cannabis use history, and their “most difficult” cannabis quit attempt.Results: 42.4% of subjects had experienced a lifetime withdrawal syndrome, of whom 70.4% reportedusing cannabis in response to withdrawal. During the index quit attempt, 95.5% of subjects reported≥1 individual withdrawal symptom (mean [SD] 9.5 [6.1], median 9.0); 43.1% reported ≥10. Number ofwithdrawal symptoms was significantly associated with greater frequency and amount of cannabis use,
but symptoms occurred even in those using less than weekly. Symptoms were usually of ≥ moderateintensity and often prompted actions to relieve them. Alcohol (41.5%) and tobacco (48.2%) were usedmore often than cannabis (33.3%) for this purpose. There was little change during withdrawal in use ofother legal or illegal substances.Conclusions: Cannabis withdrawal is a common syndrome among adults not seeking treatment. The inten-tion to relieve withdrawal symptoms can drive relapse during quit attempts, giving cannabis withdrawal
arget
clinical significance as a t
. Introduction
Cannabis is the most widely used illicit psychoactive substancen the world. An estimated 142–190 million people used cannabisn 2007 (3.3–4.4% of the population aged 15–64 years), about 10% of
hom were dependent (United Nations Office on Drugs and Crime,009). In the United States, there were an estimated 15.2 million
Please cite this article in press as: Levin, K.H., et al., Cannabis withdrawalAlcohol Depend. (2010), doi:10.1016/j.drugalcdep.2010.04.010
urrent (past month) cannabis users in 2008 (6.1% of the population2 years or older), of whom 4.2 million met DSM-IV criteria forbuse or dependence (Substance Abuse & Mental Health Servicesdministration, 2009). A majority of these current users have not
∗ Corresponding author at: National Institute on Drug Abuse, National Institutes ofealth, Intramural Research Program, 251 Bayview Boulevard, suite 200, Baltimore,D 21224, USA. Tel.: +1 443 631 8004; fax: +1 443 631 8037.
E-mail address: [email protected] (D.A. Gorelick).1 Currently at Tulane University School of Medicine, 1430 Tulane Avenue,ew Orleans, LA 70112, USA.
376-8716/$ – see front matter. Published by Elsevier Ireland Ltd.oi:10.1016/j.drugalcdep.2010.04.010
of treatment.Published by Elsevier Ireland Ltd.
sought treatment to stop their cannabis use (Stinson et al., 2006).Research has now established withdrawal from cannabis as a
distinct clinical phenomenon (Budney, 2006; Budney and Hughes,2006). This research has used several approaches, including ret-rospective self-report studies (Copersino et al., 2006a; Hasin etal., 2008), prospective outpatient self-report studies (Budney etal., 2003; Kouri and Pope, 2000; Vandrey et al., 2008), prospec-tive inpatient observational studies (Milin et al., 2008), and humanlaboratory studies of directly observed cannabinoid administrationand abstinence (Haney et al., 1999; Jones et al., 1976, 1981; Nowlanand Cohen, 1977). All these approaches demonstrate distinct with-drawal symptoms following abrupt cessation of cannabis use.Furthermore, these abstinence symptoms resolve with cannabi-
symptoms in non-treatment-seeking adult cannabis smokers. Drug
noid re-administration (Budney et al., 2007; Haney et al., 2004,2008; Jones et al., 1981), a key characteristic of a drug withdrawalsyndrome.
More than a dozen studies have retrospectively evaluated theprevalence of individual symptoms of cannabis withdrawal over a
ifetime or past year. These studies fall into three general types. Fourarge-scale (sample sizes 739–1735) studies involved adults not inreatment: subsets of the National Epidemiologic Survey on Alco-olism and Related Conditions (NESARC) with current (Agrawalt al., 2008) or frequent peak lifetime cannabis use (Hasin et al.,008); a subset of the Collaborative Study on the Genetics of Alco-olism (COGA) with more than minimal lifetime cannabis usemost with lifetime substance abuse and/or psychiatric comorbid-ty) (Wiesbeck et al., 1996); and one study involving a mixture of theeneral population and patients in treatment (Mennes et al., 2009).even smaller-scale (sample sizes 39–214) studies involved adoles-ents (Chung et al., 2008; Cornelius et al., 2008; Crowley et al., 1998;ikulich et al., 2001; Vandrey et al., 2005) or adults (Arendt et al.,
007; Budney et al., 1999) in treatment, many with substance abuser psychiatric comorbidity. Two smaller-scale studies (sample sizes7 and 104) evaluated adult, non-treatment-seeking cannabis usersithout substance abuse or psychiatric comorbidity (Vandrey et al.,
008; Copersino et al., 2006a). Of these studies, none included lessrequent (weekly or less) cannabis users and only one focused on apecific withdrawal episode (Copersino et al., 2006a) or reported onhe time course of withdrawal symptoms (Copersino et al., 2006a)r changes in other substance use during withdrawal (Copersino etl., 2006b).
Relief of withdrawal symptoms has long been considered aegative reinforcer for continued use of substances such as alco-ol and opiates (Schuster, 1975; Thompson and Pickens, 1975;icero, 1980). Several studies based on retrospective self-report
ound cannabis users reporting use to relieve or avoid cannabisithdrawal symptoms, suggesting that cannabis withdrawal can
lso serve as a negative reinforcer for cannabis use (Chung etl., 2008; Coffey et al., 2002; Cottler et al., 1995; Crowley et al.,998; Copersino et al., 2006a; Gillespie et al., 2007; Mikulich etl., 2001; Swift et al., 1998, 2001). However, a prospective study of6 cannabis-dependent outpatients who had not used other drugsr abused alcohol in the prior month found that total withdrawaleverity (product of number of withdrawal symptoms × symptomeverity [on a 4-point Likert scale]) was not significantly associ-ted with relapse over an average 2-year follow-up period (Arendtt al., 2007). Most of these studies involved patients in treatmentor cannabis abuse/dependence, and none evaluated the use ofannabis in association with specific withdrawal symptoms; onlyne evaluated changes in use of other psychoactive substances dur-ng the withdrawal period (Copersino et al., 2006b).
The present study used a more detailed version of the Mari-uana Quit Questionnaire used previously by this research groupCopersino et al., 2006a) to evaluate the experience of cannabisithdrawal by retrospective self-report in a convenience sample
f 469 adults. Subjects provided information about their lifetimeithdrawal experience, as well as detailed information about with-rawal during their single most difficult quit attempt outside aontrolled environment. Compared to prior published studies, ourtudy provides a more comprehensive evaluation of a specific with-rawal episode in a large sample of non-treatment-seeking, adultannabis users without current substance abuse or psychiatricomorbidity. This information addresses some issues relevant tohe development of DSM-V (Budney, 2006; Budney and Hughes,006). How often does cannabis withdrawal occur in nondaily usersf cannabis? What is the co-occurrence of cannabis withdrawal andannabis tolerance? Does cannabis withdrawal evoke changes inannabis and other substance use?
Please cite this article in press as: Levin, K.H., et al., Cannabis withdrawalAlcohol Depend. (2010), doi:10.1016/j.drugalcdep.2010.04.010
. Methods
.1. Subjects
Subjects were a convenience sample of 500 non-treatment-seeking cannabismokers in the Baltimore, MD area recruited from the community by advertising
PRESSependence xxx (2010) xxx–xxx
(49.7% print, 14.5% television, 0.6% radio, and 0.6% internet), word-of-mouth (20.0%),and referral from other agencies (1.7%) (12.7% unknown). Eligible subjects were 18years or older, able to read English at an 8th grade level, and had made at least oneattempt to stop all cannabis use without formal treatment while not in a controlledenvironment. All subjects were primarily cannabis users with no other current sub-stance use disorder except nicotine dependence (based on response to telephonescreening questions).
This study was approved by the Institutional Review Board of the National Insti-tute on Drug Abuse Intramural Research Program. Subjects gave written informedconsent while not acutely intoxicated or in withdrawal and were paid for their studyparticipation.
2.2. Procedures and instruments
The Marijuana Quit Questionnaire (MJQQ) is a self-report questionnaire thatcollects information in three domains: sociodemographic characteristics, historyof cannabis use (including any associated problems), and characteristics of sub-jects’ “most difficult” (self-defined) quit attempt outside a controlled environment,including reasons for quitting, coping strategies to help quit, withdrawal symptoms,and substance use before and during the quit attempt. The questionnaire has fivemodules:
1. sociodemographic information,2. cannabis use history,3. cannabis-associated problems,4. cannabis quitting experience during their most difficult quit attempt outside
a controlled setting, including withdrawal symptoms, quitting strategies, andreasons for quitting,
5. cannabis craving at time of interview (Heishman et al., 2009).
Questions were adapted from relevant prior published studies:
1. Reasons for quitting and resuming cannabis use (Adamson and Sellman, 2003;American Psychiatric Association, 2000; McBride et al., 1994; Selden et al., 1990).
2. Cannabis-related problems (Adamson and Sellman, 2003; American PsychiatricAssociation, 2000).
3. Coping strategies used during the quit attempt (Sobell et al., 2000; Walters, 2000).4. Withdrawal symptoms experienced during the quit attempt (Budney et al., 2008;
Haney et al., 1999; Jones et al., 1981; Smith, 2002; Wiesbeck et al., 1996).5. Changes in other substance use (both licit and illicit) during the quit attempt
(O’Farrell et al., 2003).
The list of lifetime cannabis-related problems allowed generation of proxy diag-noses for lifetime cannabis abuse or dependence. These included tolerance (“Haveyou ever found that you needed to use a lot more marijuana to get high than you didwhen you first started using it?”), withdrawal (“Has stopping or cutting down onmarijuana use ever made you feel sick or given you withdrawal symptoms?”), andwithdrawal relief (“After not using marijuana for a while, did you ever use it againto keep yourself from feeling sick or getting withdrawal symptoms?”). Subjects whoendorsed lifetime experience of at least one problem from among the abuse criteriain DSM-IV were considered to have cannabis abuse. Subjects who endorsed lifetimeexperience of at least three problems from among the dependence criteria in DSM-IV were considered to have cannabis dependence. These must be considered proxyor tentative diagnoses because the DSM-IV criterion that the criteria occur within a12-month interval was not assessed.
Subjects received a list of 40 possible withdrawal symptoms. If the symptom hadbeen experienced, subjects indicated the number of days after last using cannabisthat the symptom first appeared, its maximum intensity (on a 5-point Likert scalefrom “very little” to “very high”), the time of maximum intensity, the time that thesymptom disappeared, and what, if anything, was done to relieve the symptom.
The MJQQ was presented on a computer monitor and took 30–45 min to com-plete.
2.3. Statistical analyses
To minimize recall bias, only withdrawal symptoms with onset within onemonth of the start of the quit attempt were included in the analyses. To avoidpotential censoring of time course data, subjects interviewed less than one monthafter the start of their quit attempt were not included in the analysis of onset, peakintensity, time of peak intensity, and duration of withdrawal symptoms (Table 1).Comparisons among subject groups used the chi-square test for categorical vari-ables and the t-test or ANOVA for continuous variables. Bivariate logistic regressionanalysis was used to evaluate the association between continuous cannabis use vari-
symptoms in non-treatment-seeking adult cannabis smokers. Drug
ables and likelihood of experiencing lifetime cannabis withdrawal or the severityof withdrawal (number of withdrawal symptoms reported) during the index quitattempt. Multivariate linear regression analysis was used to evaluate the associationbetween demographic and cannabis and tobacco use variables and severity of with-drawal during the index quit attempt. Because number of withdrawal symptomswas not normally distributed, this variable was log transformed (with 0.5 added to
ero values to allow log transformation). Pearson’s r statistic was used to evaluatehe correlation between frequency of cannabis use and number of withdrawal symp-oms. All statistical analyses were performed with SAS statistical software version.1 (SAS Institute, Cary, NC). The two-tailed alpha level was set at 0.05.
. Results
.1. Subjects
Of the 922 individuals initially screened by telephone, 60 wereneligible and 5 were not interested in participating. Among theemaining 857 individuals scheduled for study sessions, 357 didot appear for their appointment. Of the 500 subjects consented, 2id not complete the study and 29 were discovered to be ineligible:4 had never made a quit attempt and 15 had quit in a controllednvironment such as jail or hospital. The remaining 469 subjectsrovided the data presented in this paper.
The 469 subjects were largely young adult (mean [SD] age 31.210.3] years, range 18–65 years, 16.9% <21 years old, 39.9% 21–29,9.6% 30–39, 18.6% 40–49, 4.9% 50–65) African-Americans (79.5%),ith 58% male and 42% female. The sample was generally of low
ocio-economic status. Mean years of education was 11.8 [2.1];lmost one-third (30.1%) had not completed high school, almostalf (47.5%) were high graduates, and less than one-quarter (22.6%)ad any college. Half (49.9%) the subjects were unemployed, 35.4%ere employed full or part-time, 6.6% were students, and the
emainder were disabled, retired, or homemakers. Almost three-uarters (73.1%) were never married and 11.5% were married.
The sample was skewed towards frequent cannabis users. Only.4% reported lifetime use ≤100 times; 22.4% had used 100–999imes, 43.3% 1000–10,000 times, and 27.9% more than 10,000.annabis preparations used included marijuana (88.7%), blunts62.9%), hashish (39%), and hashish oil (14.5%).
Almost all subjects (98.5%) met at least one lifetime criterion forSM-IV cannabis dependence; 90.6% met at least 3 criteria, sug-esting a likely lifetime diagnosis of cannabis dependence. Of these,1.4% met criteria for physiological dependence (i.e., with tolerance79.7%] or withdrawal [42.4%]).
At the time of interview, 397 (84.6%) subjects had used cannabisn the prior month and 266 (56.7%) in the prior week, including 8117.3%) subjects who used on the day of interview. Fifty-five (11.7%)ubjects had been continuously abstinent since their quit attempt.
.2. Characteristics of quit attempt
The index (“most difficult”) quit attempt started 41.4 [70.1]onths (median 12 months, range 2 days to 35 years) before the
nterview, and lasted 14.5 [41.8] months (median 2 months, range 1ay to 35 years). 37 subjects were interviewed less than one monthfter the start of their quit attempt (13 within one week). At the startf the quit attempt, subjects were 27.7 (9.1) years old (range 10–64ears) and had been using cannabis regularly (i.e., at least weekly)or 11.3 (8.8) years (range 0–42 years). Seven subjects were not yetsing cannabis regularly at the time of their quit attempt. Almostll subjects were smoking blunts (57.1%) or marijuana (40.5%). Overhe 6 months prior to the quit attempt, almost two-thirds of sub-ects (65.2%) averaged daily smoking; another 30.1% smoked ateast weekly. Subjects used cannabis on 22.6 [10.4] days (median0, range 1–31) in the month prior to the quit attempt, averaging.8 [4.5] (median 2.5, range 0–50) joints per occasion and 8.7 [10.5]median 6, range 1–120) joints per day.
Please cite this article in press as: Levin, K.H., et al., Cannabis withdrawalAlcohol Depend. (2010), doi:10.1016/j.drugalcdep.2010.04.010
Most subjects used legal psychoactive substances over the 6onths prior to the quit attempt: 69.7% used caffeine (36.3% at
east five days per week), 75.3% alcohol (15.3%), and 79.3% tobacco62.0%). There was minimal use of medications or illegal drugs:.7% used sedatives (0.8% at least five days per week), 7.5% over-
One hundred and ninety-nine (42.4%) subjects reported alifetime experience of cannabis withdrawal. Greater lifetimecannabis use was associated with significantly greater likeli-hood of experiencing withdrawal (chi-square = 21.3, df = 9, p = 0.01).For example, among subjects reporting at least 2000 lifetimeuses of cannabis, 49.1% experienced lifetime withdrawal, whileonly 37.1% of those with 100–1999 lifetime uses and 13.3% ofthose with less than 100 lifetime uses reported lifetime with-drawal.
There was a similar positive association between precedingcannabis use and severity of the index withdrawal episode. Greaterseverity, as reflected in the number of withdrawal symptomsreported during the quit attempt, was associated with longer dura-tion of regular (at least weekly) cannabis use (r = 0.12, p = 0.01),higher frequency of cannabis use over 6 months (r = 0.20, p < 0.0001)or one month (r = 0.15, p = 0.0009), or more joints smoked perday prior to the quit attempt (r = 0.10, p = 0.04). In the multi-variate analysis, only sex and frequency of preceding cannabisuse were significantly associated with withdrawal severity. Menhad 19% fewer withdrawal symptoms than women, and cannabisuse more frequently than weekly was associated with about 80%more withdrawal symptoms. Race, age at start of quit attempt,frequency of preceding tobacco use, and other cannabis usevariables had no significant association with withdrawal sever-ity.
Lifetime cannabis withdrawal was significantly associated withlifetime cannabis tolerance (chi-square = 14.4, df = 1, p = 0.0001).Almost half (46.8%) of subjects experiencing tolerance also reportedwithdrawal, compared with 25.3% of those not experiencing tol-erance. Conversely, the majority (87.9%) of subjects experiencingwithdrawal also reported tolerance. Subjects reporting a cannabis“hangover” (“ever needed to use marijuana in the morning toget yourself going after a heavy session of using marijuana?”) orlifetime cannabis-associated problems were also more likely toexperience withdrawal: 52.9% vs. 25.3% (chi-square = 34.5, df = 1,p < 0.0001) and 47.9% vs. 33.5% (chi-square = 9.4, df = 1, p = 0.002),respectively. No other subject characteristic, including type ofcannabis preparation used, was significantly associated withwithdrawal. There was a non-significant trend for women andAfrican-Americans to be more likely than other subjects to experi-ence withdrawal: 47.2% (women) vs. 39.0% (men) (chi-square = 3.2,df = 1, p = 0.075) and 45.0% (among African-Americans) vs. 31%(among whites) vs. 36% (among others) (chi-square = 5.3, df = 2,p = 0.07), respectively.
3.4. Individual withdrawal symptoms
95.5% of all subjects experienced at least one of the 40 indi-vidual withdrawal symptoms during their index quit attempt(Table 1). Among subjects reporting any withdrawal symptom,the mean number of symptoms was 9.5 [6.1] (median 9.0, range1–38). Almost all subjects reported more than one symptom:91.3% reported at least two, 85.1% at least three, 79.1% at least
symptoms in non-treatment-seeking adult cannabis smokers. Drug
four, 73.6% at least five, and 43.1% ten or more. The com-monest symptoms were psychological: cannabis craving (75.7%),mood changes (33.7–50.1%), sleep disturbances (21.8–46.9%), anddecreased appetite (38.8%) (Table 1). The commonest physi-cal symptoms were weight gain (23.5%) and headache (23.2%).
Weight gain (110) 6.4% (7) 2.7% (3Weight loss (71) 12.7% (9) 4.2% (3Other (37) 20.0% (4) 15.0% (
xcept for weight loss (15.1%) and upset stomach (13%), nother physical symptom occurred in more than 10% of subjectsTable 1).
The onset of acute symptoms (i.e., excepting improved memorynd weight change) ranged from one day to one week after the startf the quit attempt, with peak symptom intensity two days to twoeeks thereafter (Table 1). The duration of withdrawal symptomsas highly variable, ranging from 1.5 weeks to more than one year
Table 1). Physical symptoms and aggressive behaviors tended toave quicker onset, quicker peak intensity, and shorter durationhan sleep disturbances or mood changes (Table 1).
Mean peak intensity ratings ranged from 2.7 to 4.2 across the0 symptoms (Table 1). At least half the subjects gave one of thewo highest intensity ratings (4 or 5 out of 5) for 22 of the symp-
Please cite this article in press as: Levin, K.H., et al., Cannabis withdrawalAlcohol Depend. (2010), doi:10.1016/j.drugalcdep.2010.04.010
oms (data not shown). Every symptom had at least one-quarter ofubjects assign one of the two highest ratings. Physical symptomsended to have the lowest mean intensity ratings (Table 1) and theowest proportions of subjects assigning high intensity ratings (dataot shown).
At least half the subjects reporting a withdrawal symptom tookaction to relieve that symptom, with the exception of improvedmemory (probably not a true withdrawal symptom), strange orvivid dreams, and decreased appetite or sex drive (Table 1).
3.5. Relapse in response to withdrawal
One hundred and forty subjects (70.4% of those experiencing alifetime withdrawal syndrome) reported cannabis use in responseto withdrawal. There were no significant associations between suchrelapse and lifetime cannabis use, tolerance, cannabis “hangover,”or cannabis-associated problems.
The proportion of subjects who reported using cannabis torelieve a withdrawal symptom during their index quit attempt
symptoms in non-treatment-seeking adult cannabis smokers. Drug
varied from 0% to 25.5% for physical symptoms (median 14.7%)to 13.3–22.8% (median 16.6%) for mood symptoms and 7.8–33.3%(median 13.3%) for sleep symptoms (Table 2). There was no obvi-ous association between any specific withdrawal symptom andcannabis use (Table 2).
.6. Other substance use in response to withdrawal symptoms
Subjects were more likely to use alcohol or tobacco, rather thanannabis, to relieve most withdrawal symptoms, except for physi-al symptoms (Table 2). Overall, 186 (41.5%) subjects reported usinglcohol to relieve at least one withdrawal symptom; 216 (48.2%)sed tobacco to relieve a symptom. Sedatives, stimulants or anti-epressants were used by less than 5% of subjects (Table 2). Duringhe quit attempt, a minority of subjects increased their existingse of substances without necessarily attributing it to withdrawalelief: 16.8% increased their use of caffeine, 33.7% alcohol, and 37.7%obacco. Less than 5% of subjects started or increased their use ofllegal drugs or prescription medications; 7.9% increased their usef non-opioid pain medications.
Few subjects decreased existing use of substances during theuit attempt: 7.9% decreased use of caffeine, 12.6% alcohol, 10.2%obacco, 0.9% sedatives, 1.5% over-the-counter sleep medication,.7% stimulants, 2.8% opioid pain medication, 2.6% illegal opioids,.2% non-opioid pain medication, 2.8% hallucinogens, 1.1% phency-lidine, and 0.9% other substances.
. Discussion
This study found high rates (42.4%) of lifetime cannabis with-rawal, and of single (95.5%) and multiple (91.3%) withdrawalymptoms after the index quit attempt, in a convenience sam-le of 469 non-treatment-seeking adults. Psychological symptoms,.g., cannabis craving (75.7%) and mood changes (33.7–50.1%), andleep disturbances (20.1–46.9%) were substantially more prevalenthan physical symptoms (2.1–13.0%), except for headache (23.2%)nd weight gain (23.5%) (Table 1). Symptoms began within oneay to one week of quitting, with physical symptoms tendingo have quicker onset and shorter duration than other types ofymptoms. More than two-thirds (70.4%) of those experiencingifetime withdrawal, and up to one-third of those reporting spe-ific withdrawal symptoms during the index quit attempt, reportedannabis use in response to withdrawal, suggesting that cannabisithdrawal can serve as a negative reinforcer for relapse. Thesendings confirm and extend previous results in smaller samples ofreatment-seeking adolescents and adults.
The proportion of subjects experiencing cannabis withdrawals somewhat greater than that in most other studies of non-reatment-seeking adults with frequent lifetime or currentannabis use (range 15.6–40.9%) (Cottler et al., 1995; Schuckit et al.,999; Swift et al., 1998, 2000; Wiesbeck et al., 1996) and smallerhan that in two Australian studies of cannabis-dependent adults95.5%, 88.8%) (Copeland et al., 2001; Swift et al., 2001). Differencesn prevalence of true cannabis dependence and in substance abusend psychiatric comorbidity among the various study populationsay explain the discrepancy.Our findings differ somewhat from those in the larger sample
1119) of lifetime cannabis-using adults in the NESARC study (Hasint al., 2008), which found fewer subjects reporting multiple with-rawal symptoms (59.4% at least one, 44.2% at least two, and 34.1%t least three) and a lower prevalence of mood changes (6.4–19.3%)nd sleep disturbances (6.3–26.4%). These differences may be dueo a low prevalence of lifetime cannabis dependence (12.9%) inhe NESARC sample and to differences in the questionnaire used.he NESARC study asked about 18 withdrawal symptoms, fewerhan the 40 symptoms used in this study, but comparable to the
Please cite this article in press as: Levin, K.H., et al., Cannabis withdrawalAlcohol Depend. (2010), doi:10.1016/j.drugalcdep.2010.04.010
6 or 18 symptoms used by Budney et al. (2008) or Copersino et al.2006a). However, the questionnaire used in the NESARC study wasesigned for general use across all drug withdrawal syndromes;hus, it omitted some symptoms with high prevalence in othertudies (e.g., cannabis craving, irritability) and included symptoms
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not associated with cannabis withdrawal (e.g., seizures, hallucina-tions, fever, runny eyes or nose, and yawning).
The time course of retrospectively reported withdrawal symp-toms was broadly consistent with that reported in a smallerretrospective study of non-treatment-seeking adults (Copersino etal., 2006a). That study also found the onset of symptoms withinone day to one week of quitting, with physical symptoms tend-ing to have quicker onset and shorter duration than other typesof symptoms. Two small prospective studies of non-treatment-seeking adults assessed daily for six weeks or four weeks foundsymptom onset within 1–3 days of quitting, peak intensity in 2–6days, and symptom resolution within two weeks (Budney et al.,2003; Kouri and Pope, 2000). Similar to our results, one study foundthat physical symptoms tended to be less intense and to peak andresolve sooner than other symptoms (Budney et al., 2003). Theother study found that some physical symptoms lasted the entirefour weeks of the study (Kouri and Pope, 2000). We are not awareof other nonresidential studies that evaluated the time course ofcannabis withdrawal symptoms over intervals longer than fivedays.
Our data suggest that subjects were experiencing a true cannabiswithdrawal syndrome. The intensity of cannabis use (e.g., fre-quency of use, joints used per occasion or per day) prior to the quitattempt was positively correlated with the severity of withdrawal(as reflected in the number of withdrawal symptoms), as expectedfrom the pharmacological relationship between substance use andwithdrawal. Also consistent with this pharmacological relation-ship is the positive correlation between tolerance to cannabis andexperiencing withdrawal. Almost all subjects reported multiplesymptoms, suggesting that subjects were not reporting the scat-tered occurrence of nonspecific symptoms. Most symptoms had atleast moderate mean peak intensity (Table 1); many were ratedhigh or very high in intensity; and many prompted subjects to takeaction to relieve them (Table 1). These characteristics suggest thatmany of the reported withdrawal symptoms met the DSM-IV with-drawal criterion of “clinically significant distress or impairment”(American Psychiatric Association, 2000).
A minority of subjects increased their use of alcohol, tobacco,or caffeine during their quit attempt, often to relieve specificwithdrawal symptoms (Table 2). A smaller retrospective studyof non-treatment-seeking adults also found up to one-third ofsubjects increasing legal substance use during their quit attempt(Copersino et al., 2006b). In contrast, a prospective study of 19adult daily cannabis smokers who tried to reduce or quit their usewithout formal treatment found no change in alcohol or caffeineuse over the one month of daily assessment (Hughes et al., 2008).A controlled clinical trial of psychosocial treatment in 450 adultswith cannabis dependence also found no change in alcohol useassociated with abstinence (Marijuana Treatment Project ResearchGroup, 2004). Thus, whether subjects increase other substance usein response to cannabis withdrawal and abstinence remains unre-solved.
Our findings have several implications for the treatment ofcannabis dependence. Given that withdrawal symptoms may serveas negative reinforcement for relapse, patients should be monitoredfor withdrawal and significant symptoms promptly alleviated. Wedid not observe an obviously greater association between any spe-cific symptoms and relapse, but the commonest symptoms (e.g.,insomnia, depression, irritability, anxiety, and restlessness) shouldclearly be a focus of clinical attention. Many cannabis users areconcurrent users of alcohol, tobacco, and caffeine. They are at risk
symptoms in non-treatment-seeking adult cannabis smokers. Drug
for increased use during a quit attempt, with consequent adversehealth effects. Clinicians should monitor concurrent substance useand proactively work to forestall any increased use.
Our findings have several implications for the developmentof DSM-V. Cannabis tolerance and withdrawal were significantly
ssociated, but 47.5% of subjects experienced just one or the other,upporting their continuance as two separate dependence criteria.
e are not aware of any other study that evaluated the conjointistribution of these two dependence criteria in cannabis users.
Cannabis withdrawal, although common in daily users, occurredn some weekly or less frequent users (a population not included inrevious studies), suggesting that frequency of use should not limithe diagnosis of withdrawal. The initial proposed diagnostic crite-ia for DSM-V (www.dsm5.org, accessed March 19, 2010) requirecessation of cannabis use that has been heavy and prolonged.”ur findings suggest that a stringent interpretation of “heavy androlonged” may exclude some individuals who are experiencingannabis withdrawal. The proposed criteria also require experienc-ng three or more symptoms of withdrawal (from among a list ofeven) within several days after cessation of use. These require-ents are consistent with the experience of cannabis withdrawal
n our study sample, as long as “several days” is broadly interpreted.5.1% of our subjects experienced at least three withdrawal symp-oms, and the mean onset after cessation of use was 3–5 days for
ood symptoms, 3–6 days for insomnia, and 2–4 days for mosthysical symptoms.
Although subjects were living in the community, rather than in aontrolled environment, during their quit attempt, other substancese likely did not confound cannabis withdrawal. Most subjectsere using legal substances (caffeine, alcohol, and tobacco) prior
o their cannabis quit attempt, but only 7.9–12.6% decreased theirse at the time, thereby putting themselves at risk for a concur-ent withdrawal syndrome. In addition, tobacco use prior to theuit attempt was not significantly associated with number of with-rawal symptoms reported, as might be expected if concurrenticotine withdrawal were confounding reporting of withdrawalymptoms. Few subjects were using illegal drugs or psychoactiveedications (<15% in each category); even fewer (<10%) were using
t least 5 days per week (the average frequency of cannabis use inhe month prior to the quit attempt), and few (<5% in each cat-gory) decreased their drug use during the quit attempt, makinghem at low risk for another drug withdrawal syndrome. Large-cale retrospective survey studies have found little or no differencen prevalence of cannabis withdrawal symptoms between subjects
ith or without other substance dependence (Agrawal et al., 2008;asin et al., 2008).
This study has several limitations. Data were obtained by ret-ospective self-report without external corroboration, as is true ofost studies of cannabis quitting. There is evidence that cannabis
sers not in treatment give reliable retrospective self-report aboutheir cannabis use histories (Fendrich and Mackesy-Amiti, 1995;nsminger et al., 2007) and withdrawal symptoms (Mennes et al.,009). In addition, the pattern of responses to some withdrawalymptoms suggests that subjects were giving valid responses,ather than just responding from a generalized response set.here were four pairs of apparently mutually exclusive withdrawalymptoms. Only 25 (5.3%) subjects reported both increased andecreased sleep, 18 (3.8%) both increased and decreased appetite,ve (1.1%) both increased and decreased sex drive, and five (1.1%)oth weight gain and weight loss. This low rate of concurrenteporting of opposite symptoms suggests that subjects were giv-ng valid self-reports. Among the eight sleep-related withdrawalymptoms, there was a two-fold range in prevalence and time ofnset and a 2.5-fold range in time of peak effect and proportionaking action to relieve, suggesting that subjects were capable of
aking distinctions among symptoms.
Please cite this article in press as: Levin, K.H., et al., Cannabis withdrawalAlcohol Depend. (2010), doi:10.1016/j.drugalcdep.2010.04.010
Subjects were a convenience sample of cannabis users from oneity in one country, which may limit the external validity of the find-ngs. Compared with the 2000 US national household populationf current (past 12 months) cannabis users without other currentrug dependence (except tobacco) and no more than minimal use
PRESSependence xxx (2010) xxx–xxx 7
of other illegal drugs (Substance Abuse and Mental Health ServicesAdministration, 2001), subjects in this study were of similar age andgender distribution, but more likely to be African-American (79.5%vs. 12.4%) and of lower socio-economic status. Fewer study subjectswere married (11.5% vs. 26.1%), employed (35.4% vs. 80.6%), or hadcollege education (22.6% vs. 43.3%).
In summary, we found that cannabis withdrawal is a com-mon, clinically significant syndrome among adult users not seekingtreatment and without other substance abuse or psychiatric comor-bidity. Withdrawal was experienced by those using cannabis lessthan daily. Cannabis withdrawal may trigger relapse to cannabisuse and thus is a legitimate focus of treatment efforts.
Role of funding sources
This study was supported by the Intramural Research Pro-gram, National Institutes of Health, National Institute on DrugAbuse, and NIDA Residential Research Support Services ContractHHSN271200599091CADB. The funding sources had no further rolein study design; in the collection, analysis, and interpretation ofdata; in the writing of the report; or in the decision to submit thepaper for publication.
Contributors
Authors Gorelick, Levin, Copersino, and Heishman designed thestudy and wrote the protocol. Author Levin was responsible for datacollection oversight and data base management. Authors Liu andLevin performed the statistical analyses. Authors Levin and Gorelickwrote the first draft of the manuscript. Authors Copersino, Kelly,and Boggs reviewed the manuscript for substantive intellectualcontent. All authors reviewed and approved the final manuscript.
Conflict of interest
No conflict declared.
Acknowledgements
The authors thank Ms. Janeen Nichels for testing participants,Mr. John Etter for testing participants and data management, andDr. Susan Boyd for epidemiological comparison with the 2000 USnational household population.
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